The long-term goal of our research program is to elucidate the in vivo pathological significance of a novel molecular mechanism, which may be important for the regulation of genes in response to over activity of the angiotensin type 1 receptor (AT1R). Angiotensin II (AngII) is the classical mediator of the effects of the renin- angiotensin system on the cardiovascular homeostasis. This receptor regulates gene expression targeted by the AT1R blockers (ARB), a widely used class of anti-hypertensive drugs that are currently in trial for heart failure (HF) prevention. Inhibition of AT1R in vascular, renal, neuronal and cardiac cells by ARBs protects, but unregulated AT1R activation causes disease states such as hypertension, renal failure, cardiac hypertrophy and progression to HF. We have discovered a novel AT1R signaling paradigm, wherein, Gaa2?12 mobilizes into the nucleus. In the nucleus, G[unreadable]2 functions as an epigenetic modulator of gene expression programs. Thus, G[unreadable]2?12 appears to function as a novel AT1R-to-nucleus messenger that mediates AngII-induced regulation of genes. The goal of this project is to understand the in vivo significance of hither-to-unknown consequences of G[unreadable]2 functions in the nucleus which may be useful for targeted therapy. Currently, it is unknown whether G[unreadable]2 translocation is prevalent in human disease states. No experimental models for studying enhanced G[unreadable]2 functions in the nucleus exist and there are no pharmacological tools to modulate G[unreadable]2 interactions with nuclear targets. To overcome these barriers would require high-risk innovation. The overall objectives of this application are to validate the relevance of the phenomenon in a human disease state;develop new experimental models to study the role of G[unreadable]2 in the nucleus and to develop small molecules to modulate nuclear functions of G[unreadable]2. Our central hypothesis is that exaggerated nuclear translocation of G[unreadable]2 contributes to sustained or "chronic" transcriptional activation leading to pathophysiological responses. We will pursue the following specific aims;(i) Determine interactions of G[unreadable]2 in the nuclear proteome of in vivo disease models including human heart failure samples;(ii) Evaluate pathological consequences of enhanced G[unreadable]2 function in the nucleus in a novel transgenic mouse model;(iii) Develop small molecule probes for disrupting G[unreadable]2 interaction with transcription factors. If the AT1R activity is not regulated properly, AngII stimulus becomes chronic and can damage the tissue, as well as contribute to chronic disorders of myocardium. A clear understanding of novel transcription regulatory mechanisms is important to improve the therapeutic application of ARBs. These proposed studies will advance our knowledge of AT1R biology. PUBLIC HEALTH RELEVANCE: The angiotensin type 1 receptor (AT1R) for the vasoactive hormone AngII is a regulator of gene expression targeted by the angiotensin receptor blockers (ARB), a class of anti-hypertensive drugs. Inhibition of AT1R by ARBs protects against, but unregulated AT1R activation causes disease states such as hypertension, renal failure, cardiac hypertrophy and progression to heart failure. We have discovered a novel AT1R signaling paradigm, wherein, G[unreadable]2?12 mobilizes into the nucleus. In the nucleus, G[unreadable]2 functions as an epigenetic modulator of gene expression programs. In this proposal we will be investigating the novel epigenetic control of transcription linked to disease states. These studies are necessary to understand mechanisms of progression of cardiovascular diseases, and to identify new drug targets for intervention. Fatalities from cardiovascular diseases remain a public health concern and adequate treatment for their reversal is currently lacking.